What is the role of leukotrienes in asthma and how are leukotriene‑modifying agents used in treatment?

Role of Leukotrienes in Asthma and Clinical Use of Leukotriene-Modifying Agents

Leukotrienes are potent inflammatory mediators that drive the core pathophysiology of asthma through bronchoconstriction, mucus hypersecretion, airway edema, and eosinophil recruitment, but leukotriene-modifying agents should be reserved as alternative or add-on therapy rather than first-line treatment because inhaled corticosteroids demonstrate superior efficacy across all clinically meaningful outcomes.

Pathophysiologic Role of Leukotrienes

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are synthesized from arachidonic acid by eosinophils and mast cells and bind to CysLT1 receptors located on airway smooth muscle cells, airway macrophages, and other pro-inflammatory cells 1. These mediators produce multiple effects that directly contribute to asthma pathology:

• Airway smooth muscle contraction and bronchoconstriction, representing some of the most potent bronchoconstrictors identified 1, 2, 3
• Increased mucus production and hypersecretion 2, 4, 5
• Enhanced vascular permeability leading to airway edema 2, 4
• Chemotaxis and recruitment of eosinophils and neutrophils into airways 6, 2, 4
• Airway smooth muscle cell proliferation 4
• Increased bronchial hyperresponsiveness 4, 5

LTB4 specifically functions as a chemoattractant for neutrophils and eosinophils, while cysteinyl leukotrienes can be measured in bronchoalveolar lavage fluid, blood, urine, and sputum from asthmatic patients 2.

Mechanism of Leukotriene-Modifying Agents

Two distinct pharmacologic approaches target the leukotriene pathway:

Leukotriene Receptor Antagonists (LTRAs)

• Montelukast and zafirlukast bind with high affinity and selectivity to the CysLT1 receptor, blocking the physiologic actions of LTD4 without agonist activity 1, 3, 5
• These agents reverse the primary biological effects of cysteinyl leukotrienes including bronchoconstriction, mucus hypersecretion, and airway inflammation 7

5-Lipoxygenase Inhibitors

• Zileuton inhibits 5-lipoxygenase, the enzyme catalyzing leukotriene formation from arachidonic acid, thereby blocking synthesis of LTB4, LTC4, LTD4, and LTE4 2, 3
• Both R(+) and S(-) enantiomers of zileuton are pharmacologically active as 5-lipoxygenase inhibitors 2
• In patients receiving zileuton 600 mg four times daily, peak plasma levels averaging 5.9 mcg/mL were associated with 98% mean LTB4 inhibition 2

Clinical Positioning in Asthma Management

First-Line Therapy Hierarchy

Inhaled corticosteroids (ICS) remain the preferred first-line controller medication for persistent asthma, with leukotriene modifiers considered only as alternatives when patients cannot or will not use ICS 8. This recommendation is based on compelling comparative efficacy data:

• Low-dose ICS (fluticasone, budesonide, or beclomethasone) are significantly more effective than montelukast across all key outcomes including lung function, symptom control, and exacerbation reduction 8
• The PACT study demonstrated fluticasone monotherapy was superior to montelukast with a Number Needed to Treat of approximately 6.5 8
• In children with mild-to-moderate persistent asthma, only 5% responded to montelukast alone compared to 23% who responded to fluticasone alone 8

Specific Clinical Scenarios Where Leukotriene Modifiers Show Efficacy

Leukotriene-modifying drugs demonstrate particular effectiveness in certain asthma phenotypes:

• Exercise-induced bronchoconstriction: LTRAs effectively prevent exercise-induced bronchospasm 6, 5, 7
• Aspirin-sensitive asthma: These agents modify the pulmonary reaction to aspirin in sensitive subjects 5, 7
• Allergen-induced bronchoconstriction: They attenuate the airway response to inhaled antigen 5
• Cough-variant asthma: Leukotriene receptor antagonists appear particularly effective in treating cough due to asthma 6

Add-On Therapy Role

For patients with inadequate control on ICS monotherapy:

• Long-acting beta-agonists (LABAs) are the preferred add-on agent to ICS for patients ≥12 years 8
• Leukotriene modifiers represent an alternative adjunctive therapy but are not the preferred option 9
• For step 3 therapy, zileuton is an alternative adjunctive therapy with low-dose ICS, but LABAs are preferred 9
• Leukotriene modifiers were shown effective in controlling symptoms of mild to moderate asthma and reducing the use of asthma medication, though a large number of patients from 2-3 studies was needed to show only a 5% difference from placebo 6

Steroid-Sparing Potential

Leukotriene modifiers have demonstrated potential steroid-sparing effects and additive benefit in symptomatic moderate asthmatics on maintenance inhaled corticosteroids 7. However, the combination of intranasal plus intra-bronchial corticosteroids should remain current clinical practice pending more research 6.

Agent-Specific Considerations

Montelukast

• Generally considered safe with no specific adverse effects for the majority of patients 10
• The FDA has issued warnings about serious neuropsychiatric events, including suicidal thoughts or actions, requiring monitoring for unusual behavioral or mood changes, particularly in children and adolescents 10
• Does not require liver function monitoring 10

Zafirlukast

• Postmarketing surveillance has documented cases of reversible hepatitis and, rarely, irreversible hepatic failure resulting in death and liver transplantation 10
• Hepatic monitoring is essential due to documented hepatotoxicity risk 10

Zileuton

• Not approved for children under 12 years of age 9
• Liver function monitoring is essential and mandatory 9, 10
• Elevation of liver enzymes is the primary concern, with limited case reports documenting reversible hepatitis and hyperbilirubinemia 10
• Can inhibit metabolism of warfarin and theophylline; doses of these drugs must be monitored accordingly 9
• Is a less desirable alternative because of limited studies as adjunctive therapy and the need to monitor liver function 9

Critical Clinical Algorithm

For mild persistent asthma (symptoms >2 days/week but not daily):

• Start with low-dose ICS as first-line therapy 8
• Consider leukotriene modifiers only if ICS cannot be used or patient refuses ICS 8

For moderate persistent asthma (daily symptoms):

• Use medium-dose ICS or low-dose ICS + LABA as first-line 8
• Leukotriene modifiers may be added as third-line adjunctive therapy if control remains inadequate 9

For specific phenotypes:

• Exercise-induced asthma: Consider leukotriene modifiers as targeted therapy 6, 5, 7
• Aspirin-sensitive asthma: Leukotriene modifiers are particularly suitable 4, 7
• Cough-variant asthma: LTRAs appear particularly effective 6

Important Limitations and Caveats

Leukotriene modifiers have limited anti-inflammatory potency compared to corticosteroids:

• There is little evidence that these medications have potent anti-inflammatory activity 5
• Corticosteroids are believed to be the most potent anti-inflammatory agents available, though they do not suppress all inflammatory mediators involved in the asthmatic response 4
• Leukotriene synthesis or release is unaffected by corticosteroid administration, providing a mechanistic rationale for combination therapy 4

The positioning of leukotriene modifiers in relationship to inhaled corticosteroids in the treatment of asthma has not been fully defined but continues to emerge with further study and clinical use 5.